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Chapter 5 : Antibiotics That Block DNA Replication and Repair: the Quinolones

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Abstract:

Inhibition of DNA replication and repair enzymes would seem a logical target for antibacterial action by natural products elaborated by microbes to kill their neighbors. One such class of molecules, the coumarins, represented by such streptomycete metabolites as novobiocin and coumermycin, has been studied for many years and served to pinpoint enzymes called DNA type II topoisomerases, specifically DNA gyrase, as the killing target. The newest generation of quinolones in particular, such as gatifloxacin, have increased potency against gram-positive pathogens. Thousands of fluoroquinolones have been synthesized around the core planar heterocyclic nucleus that gives the family its name. Extensive analysis has indicated that quinolones affect the double-strand cleavage/double-strand religation equilibrium in gyrase and topo IV catalytic cycles, such that the cleaved complex accumulates. There has been speculation about whether quinolones speed up the double-cleavage step of bound DNA or selectively slow the double-religation step, without definitive evidence for either interpretation. The mechanism by which quinolones induce the accumulation of the doubly cut covalent DNA-enzyme intermediate is likewise still mysterious. As the quinolone-covalent gyrase-doubly cut DNA intermediate accumulates, the killing action is thought to be from the downstream effect this block has on the progression of DNA replication forks which are halted by this. It may be that DNA repair machinery is recruited, attempts to come to the rescue, and fails as the recalcitrant quinolone-stabilized gyrase-DNA intermediate persists. This may be the signal that turns on the signaling processes that lead to the rapid killing of bacteria induced by the quinolones.

Citation: Walsh C. 2003. Antibiotics That Block DNA Replication and Repair: the Quinolones, p 70-77. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch5

Key Concept Ranking

DNA Repair Enzyme
0.4985717
Bacterial DNA Replication
0.45474598
DNA Topoisomerase IV
0.43951488
Urinary Tract Infections
0.43036914
0.4985717
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Figures

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Untitled

Antibiotics that block DNA and RNA replication.

Citation: Walsh C. 2003. Antibiotics That Block DNA Replication and Repair: the Quinolones, p 70-77. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch5
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Figure 5.1

Antibiotics that inhibit DNA gyrase and topoisomerase IV: (A) aminocoumarin antibiotics; (B) quinolones (ciprofloxacin and levofloxacin); and (C) new quinolones (gatifloxacin).

Citation: Walsh C. 2003. Antibiotics That Block DNA Replication and Repair: the Quinolones, p 70-77. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch5
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Figure 5.2

Model for super-coil formation by bacterial DNA gyrase. (From Cozzarelli [1980].)

Citation: Walsh C. 2003. Antibiotics That Block DNA Replication and Repair: the Quinolones, p 70-77. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch5
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Figure 5.3

X-ray structure of the dimeric 92-kDa fragment of yeast topoisomerase II. (From Berger et al. [1996].)

Citation: Walsh C. 2003. Antibiotics That Block DNA Replication and Repair: the Quinolones, p 70-77. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch5
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Image of Figure 5.4
Figure 5.4

Schematic of DNA gyrase mechanism: (A) double-strand DNA cleavage and double covalent enzyme formation; (B) double-strand passage to lower linking number; and (C) religation of doubly cut DNA.

Citation: Walsh C. 2003. Antibiotics That Block DNA Replication and Repair: the Quinolones, p 70-77. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch5
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Figure 5.5

Possible mechanism for quinolone base stacking to stabilize the covalent enzyme intermediate with double-strand DNA cuts.

Citation: Walsh C. 2003. Antibiotics That Block DNA Replication and Repair: the Quinolones, p 70-77. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch5
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References

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Tables

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Table 5.1

Characteristics of topoisomerases

Citation: Walsh C. 2003. Antibiotics That Block DNA Replication and Repair: the Quinolones, p 70-77. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch5

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